Zinc is an essential micronutrient that is protective for human health through its actions as an antioxidant and by maintaining genomic integrity. Arsenic is a widely distributed, naturally occurring element and is one of the World Health Organization's 10 chemicals of major public health concern. Among the consequences of arsenic exposure is increased oxidative stress and DNA damage that contributes to adverse health effects. The health impact of excess arsenic and zinc deficiency overlap significantly, yet it is unknown whether low zinc status enhances susceptibility to arsenic toxicity. Based on our findings that arsenic interacts with certain zinc finger DNA repair proteins leading to inhibition f DNA repair function, we hypothesize that low zinc status and arsenic exposure will synergistically increase oxidative stress and zinc release from key DNA repair proteins leading to inhibition of DNA repair and increased DNA damage. Through the ViCTER consortium we are assembling a team of investigators with appropriate expertise to study the consequences and mechanisms of toxicity due to combined zinc deficiency and arsenic exposure. Project 1 will investigate how zinc deficiency may enhance arsenic-induced oxidative stress leading to inhibition of DNA repair processes mediated by zinc finger DNA repair proteins. Project 2 will study whether low zinc status sensitizes response to arsenic toxicity in a rodent model. Project 3 will investigate the relationship between zinc status and biomarkers of arsenic toxicity in participants in the Navajo Birth Cohort Study. Low zinc status and arsenic exposure has been documented in study participants through direct metal bio monitoring conducted within the Birth Cohort Study. This ViCTER consortium will involve three highly interactive projects which significantly expand the original aims of the parent RO1 grant. We will build upon the strengths of our respective institutions to investigate a novel mechanism of arsenic toxicity. Furthermore, we will test the central hypothesis in cells, animal models and within a human population and achieve synergy by integrating measures of oxidative stress and DNA damage response across the experimental systems and within the study population. The expected positive impact of the study will arise from improved mechanistic understanding of functional interactions between arsenic and zinc, the potential to identify functional biomarkers of low zinc status that could be applied in population settings, and development of the scientific justification to support a future interventional study in an affected population. If the aims of the study are met, we will obtain valuable insights on whether low zinc status is a potential risk factor for arsenic toxicity.